The invention relates to the allylic oxidation of organic compounds.
Allylic oxidation is a fundamental organic reaction of significant interest to organic chemists practicing in a variety of fields from agricultural products to pharmaceuticals. A variety of procedures are known for oxidizing various organic compounds that possess allylically activated hydrogen, but such procedures typically suffer from unsatisfactory yields, tedious workups and/or require the use of expensive and/or ecologically and physiologically undesirable reagents, such as chromium.
Hence, a continuing need exists for a simple, efficient, safe and cost-effective procedure for selectively effecting allylic oxidation of organic compounds.
We have discovered a simple, efficient, safe, cost-effective and ecologically friendly procedure for oxidizing organic compounds having allylic hydrogen atom(s). The procedure involves reactively contacting the organic compound with a combination of periodic acid or metal periodate and an alkyl hydroperoxide under conditions sufficient to effect oxidation of the allylic hydrogen(s) on the organic compound.
The reaction is conveniently conducted in a cosolvent system of water and organic solvent(s), and is usually conducted at ambient temperature and normal pressure conditions. However, the yield of the desired product can generally be further improved and/or the reaction process facilitated by conducting the reaction under increased pressure and/or above ambient temperature.
Definitions
As utilized herein, including the claims, the term xe2x80x9callylic compoundxe2x80x9d references an organic compound having at least one allylic hydrogen atom.
As utilized herein, including the claims, the term xe2x80x9callylic oxidationxe2x80x9d means oxidation of an allylic compound by replacing the allylic hydrogen(s) with oxygen or an oxygen containing group.
As utilized herein, including the claims, the term xe2x80x9creactantsxe2x80x9d collectively references allylic compound, periodic acid or metal periodate and alkyl hydroperoxide. Solvents, including both organic solvent(s) and water, are specifically excluded from the definition of reactants.
As utilized herein, including the claims, xe2x80x9c(v/v)xe2x80x9d refers to the volumetric percentage of water to total water miscible solvent(s).
Process
The process involves reactively contacting an allylic compound with a metal periodate or periodic acid and an alkyl hydroperoxide under conditions of normal to increased pressure of air or nitrogen and/or zero to above ambient temperature to effect allylic oxidation of the allylic hydrogen atom(s) on the organic compound. For example, the allylic compound can be allylically oxidized by (i) dissolving the allylic compound in a suitable mixture of a water miscible organic solvent, a water immiscible organic solvent and the alkyl hydroperoxide, (ii) incorporating the periodic acid or metal periodate and a suitable amount of water into the reaction mixture, and then (iii) optionally pressurizing the reaction vessel with air or nitrogen. In the case of metal periodates, water gradually dissolves the periodate during the course of the reaction and thereby provides the necessary reactive contact between the reactants. As an added feature, the limited solubility of metal periodate in water permits the pH of the reaction mixture to be controlled to some extent should such pH control be desired.
CONSTITUENTS
Allylic Compounds
Allylic compounds include any organic compound incorporating the structure xe2x80x94C1Rxe2x89xa1C2Hxe2x80x94C3Hnxe2x80x94 within the molecule, wherein n is 1, 2 or 3. Hydrogen atoms attached to the C1 and C2 carbon atoms are referenced as vinylic hydrogen. Hydrogen atoms attached to the C3 carbon atom are referenced as allylic hydrogen. The process of this invention selectively oxidizes allylic hydrogen atoms over vinylic hydrogen atoms. Exemplary allylic compounds include specifically, but not exclusively, (i) aliphatic vinylic compound such as methyl oleate, (ii) aromatic benzylic compounds such as fluorene and diphenyl methane, (iii) isoprenoids, such as carotenoids, terpenes, sesquiterpenes and vitamins, and (iv) steroids and sterols, such as androstenes, cholesterol, estraenes, pregnenes and derivatives thereof such as esters, ethers and ketals of these compounds.
Of particular commercial interest is the allylic oxidation of steroids, such as dehydroepiandrosterone and various derivatives of dehydroepiandrosterone, because the steroid can be allylically oxidized without the use of physiologically or ecologically hazardous materials, such as the transition metals. The invention does not contaminate the allylically oxidized product with a toxic metal.
Cooxidants
(Periodic Acid, Metal Periodate and Alkyl Hydroperoxide)
A cooxidant system of a metal periodate or a periodic acid and an alkyl hydroperoxide is used to allylically oxidize the allylic compound. The term metal periodates references salts of periodic acid with monovalent alkali metals such as sodium, divalent metals such as zinc or transition metals like iron. The required salts may be generated in the reaction in-situ, if required, by the addition of commonly available salts of the metals such as zinc acetate, ferric chloride, etc. Experimentation has shown that the specific combination of sodium periodate and butyl hydroperoxide can generally provide a superior yield and/or superior quality of allylically oxidized product under ambient reaction conditions, which can further be improved by conducting the reaction under slightly increased pressure of air or nitrogen and slightly above ambient temperature. An additional benefit provided by the use of butyl hydroperoxide is that butyl hydroperoxide is a liquid under ambient conditions and can also facilitate dissolution of the allylic compound in the organic solvent(s).
The metal periodate, periodic acid and alkyl hydroperoxide reactants are available from a number of chemical suppliers. The alkyl hydroperoxide can be conveniently utilized as an aqueous solution or even in its anhydrous form. Since the reaction mixture preferably includes water for the purpose of gradually dissolving the metal periodate during the course of the reaction, the alkyl hydroperoxide is most conveniently utilized as a 70-90 wt % aqueous solution.
Generally, a concentration of about 0.5 to about 5 mole equivalents of periodic acid or metal periodate, preferably about 1.0 to about 3 mole equivalents of periodic acid or metal periodate, and about 10 to about 15 mole equivalents of alkyl hydroperoxide are effective for allylically oxidizing an allylic compound. Concentrations of less than about 0.5 mole equivalent of periodic acid or metal periodate and less than about 10 mole equivalents of alkyl hydroperoxide significantly slows the reaction, while greater than about 3 mole equivalents of periodic acid or metal periodate and greater than about 15 mole equivalents of alkyl hydroperoxide increases the cost of the process without producing a corresponding increase in any beneficial property or characteristic of the process or resultant product(s).
Organic Solvent(s)
The organic reactants (i.e., allylic compound and alkyl hydroperoxide) can be conveniently dissolved in suitable organic solvent(s). Depending upon the specific allylic compound and alkyl hydroperoxide used, the organic compounds may be suitably dissolved in a water miscible organic solvent(s), or may require the use of a biphasic organic solvent system which includes at least one water miscible organic solvent and at least one water immiscible organic solvent.
The water miscible solvent, when utilized, is selected primarily for its ability to dissolve the organic reactants and in a biphasic system, to facilitate reactive contact between the water soluble periodic acid or metal periodate and the organic reactants solubilized in the water immiscible organic solvent. Suitable water miscible organic solvents include specifically, but not exclusively, acetone, acetonitrile, t-butanol and organic bases such as pyridine.
The water immiscible solvent, when utilized, is selected primarily for its ability to dissolve the specific allylic compound to be oxidized and to create a clear biphasic reaction mixture. A variety of suitable water immiscible solvents are available, including specifically, but not exclusively: (i) aliphatic hydrocarbons, such as petroleum ether, n-hexane, n-heptane and isooctane, and (ii) alicyclic hydrocarbons, such as cyclohexane, (iii) aliphatic alkyl esters such as ethyl acetate, and (iv) helogenated hydrocarbons such as methylene dichloride.
Water
A sufficient amount of water is preferably incorporated into the reaction mixture for the purpose of controllably dissolving the metal periodate throughout the course of the reaction. As previously referenced, the limited solubility of metal periodate in water permits the pH of the reaction mixture to be controlled to some extent in those situations where pH control is necessary or desirable.
The reaction mixture can conveniently incorporate about 10% to about 50% (v/v), preferably about 15% to about 40% (v/v), most preferably about 20% to about 30% (v/v), water. A concentration of less than about 10% (v/v) significantly slows the rate of reaction, with a complete absence of water resulting in an almost complete absence of any allylic oxidation of the allylic compound specifically in the case of oxidants involving use of metal periodates.
SOLID SUPPORT
Although the reaction is primarily conducted in an organic solvent in a single phase or in a biphasic reaction mixture involving use of a water immiscible solvent, it can also be conducted conveniently using metal periodate or periodic acid on a solid support. For this purpose, the metal periodate or periodic acid is ground in a suitable grinding device along with a solid support material. The solid support material may be selected from such commercially available support materials as alumina, silica gel, bentonite, celite, etc. In general, the ground metal periodate or periodic acid should constitute about 20% to about 60% of the solid support, more preferably about 20% to about 40% of the solid support, and most preferably about 50% of the solid support. The use of solid supports does not necessarily result in an increased yield, but does simplify work up of the reaction mixture.
PROCESSING PARAMETERS AND PROCEDURES
Reaction Time
While dependent upon a number of variables, including the specific allylic compound being oxidized, the specific cooxidants being used and the concentration of reactants within the reaction mixture, the reactions can typically be conducted in about 6 to about 48 hours.
Reaction Temperature
The reaction can normally be conducted at ambient or slightly sub-ambient conditions (i.e., temperatures between about 0-25xc2x0 C.). We have found that reaction time can be drastically reduced by conducting the reaction at elevated temperatures of between 35-65xc2x0 C., preferably about 40xc2x0 C.
In addition, we have found that the formation of xcex945-androsterone-4,7-dione derivatives, a common contaminant obtained during the oxidation of dehydroepiandrosterone derivatives, can be drastically reduced by conducting the oxidation at above ambient temperature.
Reaction Pressure
We have found that an increased yield can be obtained by conducting the reaction under conditions of elevated pressure using a suitable gas such as air or nitrogen (i.e., a pressure of greater than 1 atmosphere). The reaction is preferably conducted at a pressure of about greater than 1 to 10 atmospheres, more preferably at a pressure between 2 to 5 atmospheres, and most preferably at about 3 atmospheres. Suitable gases include air, nitrogen and combinations thereof.
A continuing increase in total yield of the product is generally observed up to a pressure of about 3 atmospheres, with pressures above about 10 atmospheres substantially increasing the cost of the processing equipment without a corresponding increase in yield. While the specific increase in yield attributable to elevated pressure depends upon a number of variables, including the specific reactants involved in the reaction, as a general matter we have found that an increase of up to 10% in total yield can be achieved.
pH
The pH of the reaction mixture can impact the yield of desired product, with the optimal pH primarily dependent upon the specific allylic compound being oxidized. Periodic acid or metal periodates are acidic reagents which tend to acidify the reaction mixture to a pH of approximately 1 to 5 depending upon the specific oxidant being used. In those cases where a more neutral pH is desired, such as when the allylic compound includes an acid sensitive group(s), the normally acidic pH of the reaction mixture can be neutralized to some extent by incorporating an organic base, such as pyridine, or a weak inorganic base, such as sodium bicarbonate, into the reaction mixture. Alternatively, the reaction can be conveniently carried out by using a solvent system of water and a water miscible organic base, such as pyridine.
Mixing
The reaction mixture should be continuously and vigorously stirred in order to promote contact between the reactants dissolved within the various solvents and thereby enhance the yield and/or quality of the desired allylically oxidized organic compound. In the absence of active mixing, we have observed a significant decrease in the yield and the quality of the desired product.
Solvent Dilution Factor
As with substantially any solvent-based reaction, the wt % solids should be retained between an upper solubility limiting percentage and a lower reaction rate limiting percentage. As the upper wt % of solids is reached, the viscosity of the resultant reaction mixture increases to such an extent that the necessary molecular interaction of the reactants are limited (e.g., the reaction mixture cannot be effectively mixed, with a resultant loss in yield and/or increased reaction time). Conversely, as the lower wt % of solids is reached, the reaction time begins to increase dramatically due to the reduced opportunity for the reactants to encounter one another within the reaction mixture. Such low concentrations of solids also results in increased expense due to the excessive amounts of solvent used per unit of reaction product obtained.
While the preferred wt % of solids in the reaction mixtures of this invention depend upon a number of variables, including the specific solvent(s) used and the specific reactants employed, a solids wt % of between about 5 wt % to about 15 wt % has been found to be generally acceptable for producing a high yield of good quality product at a reasonable rate of reaction.
Separation and Purification Techniques
Upon completion of the oxidation reaction, the oxidized allylic organic compound can be separated from the solvent system, as well as any unused reactants and any byproducts, by any of a variety of techniques known to those skilled in the art including dilution, filtration, extraction, evaporation, distillation, decantation, crystallization/recrystallization, chromatography, etc.
The excess of alkyl hydroperoxide present in the system can be decomposed, when desired, by methods known to those skilled in the art, such as (i) adding an aqueous solution of an alkali metal sulfite, (ii) adding a mixture of a mineral acid and acetic acid at sub-ambient temperatures (e.g., 0-5xc2x0 C.), or (iii) adding a solution of a transition metal salt (e.g., ferrous ammonium sulfate in water).
The separated oxidized allylic organic compound can be further purified by various known techniques such as (i) washing the separated oxidized allylic organic compound with a solvent effective for selectively dissolving any remaining contaminants without dissolving appreciable quantities of the oxidized allylic organic compound, such as water or diethyl ether, and/or (ii) crystallizing the separated oxidized allylic organic compound in a suitable solvent or cosolvents.
In the case of allylic oxidation of steroids such as dehydroepiandrosterone derivatives, the product is often contaminated with trace amounts of the corresponding 4,7-dione derivatives, which has proven difficult to remove by usual techniques such as crystallization. Hence, dehydroepiandrosterone derivatives produced in accordance with the process are best purified by treating the crude product with weak inorganic bases such as bicarbonates, or with inorganic adsorbents like alumina in an organic solvent such as a lower ketone like acetone, halogenated hydrocarbon like methylene dichloride, lower aliphatic esters like ethyl acetate, lower alkanol like methanol or a suitable combination thereof.